PDGF Synergistically Enhances IFN-γ-Induced Expression of CXCL10 in Blood-Derived Macrophages: Implications for HIV Dementia

Dhillon, Navneet K.; Peng, Fuwang; Ransohoff, Richard M.; Buch, Shilpa

doi:10.4049/jimmunol.179.5.2722

Cited by 44 publications

(49 citation statements)

References 70 publications

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“…It is interesting to note that platelet-derived growth factor expression, which is significantly upregulated in the coculture system described above, has been shown to act synergistically with IFN-γ to stimulate CXCL10 expression in other cell systems. 46 In support of our in vitro findings, we have demonstrated that CXCL10 is expressed in α-smooth muscle actin positive cells in first trimester decidual sections. Interestingly, some cells expressing CXCL10 were found at some distance from the vessel lumen.…”

Section: Il-6 Is Expressed In Myometrial Arteriessupporting

confidence: 70%

Trophoblast-Induced Changes in C-X-C Motif Chemokine 10 Expression Contribute to Vascular Smooth Muscle Cell Dedifferentiation During Spiral Artery Remodeling

Wallace

Cartwright

Begum

et al. 2013

ATVB

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Objective-During pregnancy, fetal trophoblast disrupt endothelial cell and vascular smooth muscle cell (VSMC) interactions in spiral arteries of the maternal decidua to enable increased nutritional and oxygen delivery to the fetus. Little is known regarding this transformation because of difficulties of studying human pregnancy in vivo. This study investigated how trophoblast-secreted factors affect the interactions of vascular cells and the differentiation status of VSMC during spiral arteries remodeling using 3-dimensional vascular spheroid coculture. Methods and Results-Endothelial cell and VSMC were cocultured in hanging droplets to form spheroids representing an inverted vessel lumen. Control or conditioned media from an extravillous trophoblast (EVT) cell line was incubated with vascular spheroids for 24 hours. Spheroid RNA was then analyzed by Illumina Sentrix BeadChip array. Spheroids incubated with EVT conditioned medium showed significant up/downregulation of 101 genes (>1.5-fold; P<0.05), including an upregulation of C-X-C motif chemokine 10 (IP-10). C-X-C motif chemokine 10 expression was confirmed by qualitative real-time PCR and Western blot analysis of spheroids, and immunohistochemistry of first trimester decidua and ex vivo dissected nonplacental bed spiral arteries. EVT conditioned medium reduced VSMC expression of differentiation markers, and both EVT conditioned medium and C-X-C motif chemokine 10 increased motility of VSMC indicating dedifferentiation of VSMC. Conclusion-EVT-induced

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Section: Il-6 Is Expressed In Myometrial Arteriessupporting

confidence: 70%

Trophoblast-Induced Changes in C-X-C Motif Chemokine 10 Expression Contribute to Vascular Smooth Muscle Cell Dedifferentiation During Spiral Artery Remodeling

Wallace

Cartwright

Begum

et al. 2013

ATVB

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“…These observations are intriguing given the purported role of IFN-␥ in the pathogenesis of several diseases, such as multiple sclerosis, sepsis, human immunodeficiency virus-associated dementia, and Alzheimer's (14,19,32,79,81). The results of the present study can lend insight into results from current clinical trials involving the administration of IFN-␥ as adjuvant therapy (49) and possibly the design of future trials involving IFN-␥ blockade.…”

Section: Discussionmentioning

confidence: 76%

Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production

Lin¹,

Tripathi²,

Sholl³

et al. 2009

J Virol

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Intracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-␥). Here, we assessed the role of CD4؉ T cells and IFN-␥ on immune cell recruitment and proinflammatory cytokine/chemokine production in the central nervous system (CNS) after i.c. LCMV infection. We found that T-cell-depleted mice had decreased recruitment of hematopoietic cells to the CNS and diminished levels of IFN-␥, CCL2 (MCP-1), CCL3 (MIP-1␣), and CCL5 (RANTES) in the cerebrospinal fluid (CSF). Mice deficient in IFN-␥ had decreased CSF levels of CCL3, CCL5, and CXCL10 (IP-10), and decreased activation of both resident CNS and infiltrating antigen-presenting cells (APCs). The effects of IFN-␥ signaling on macrophage lineage cells was assessed using transgenic mice, called "macrophages insensitive to interferon gamma" (MIIG) mice, that express a dominant-negative IFN-␥ receptor under the control of the CD68 promoter. MIIG mice had decreased levels of CCL2, CCL3, CCL5, and CXCL10 compared to controls despite having normal numbers of LCMV-specific CD4 ؉ T cells in the CNS. MIIG mice also had decreased recruitment of infiltrating macrophages and decreased activation of both resident CNS and infiltrating APCs. Finally, MIIG mice were significantly protected from LCMV-induced anorexia and weight loss. Thus, these data suggest that CD4 ؉ T-cell production of IFN-␥ promotes signaling in macrophage lineage cells, which control (i) the production of proinflammatory cytokines and chemokines, (ii) the recruitment of macrophages to the CNS, (iii) the activation of resident CNS and infiltrating APC populations, and (iv) anorexic weight loss.Immune cell recruitment to and infiltration of the central nervous system (CNS) is central to the pathology of a variety of inflammatory neurological diseases, including infectious meningoencephalitis, multiple sclerosis, and cerebral ischemia (59, 60). Chemokines have been shown to be highly upregulated in both human diseases and animal models of neuroinflammation and are thought to be important mediators of immune cell entry into the CNS (59, 60). (27) and serve to amplify the ongoing inflammatory response (25, 28). However, in some EAE studies, neither CCL3 nor CXCL10 were required for disease (72,73). During CNS viral infection, CXCL10 and CCL5 are highly produced in several models (2,41,48,82). In addition, mice deficient in CCR5, which binds (among others) CCL3 and CCL5, do not display impaired CNS inflammation after certain viral infections (13). Thus, the role of chemokines in CNS inflammation is likely complex and dissimilar between autoimmune and viral infection models.IFN-␥ is present in the CNS during autoimmunity and infection (7,54,69). Several studies suggest that IFN-␥ can be a potent inducer of CNS chemokine expression. Adenoviral expression of IFN-␥ in the CNS strongly induced CCL5 and CXCL10 mRNA and protein, and this induction was dependent on the presence of the IFN-␥ receptor (50). In EAE and Toxopla...

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“…TNF␣ and IFN␥ Do Not Regulate CXCL10 via Post-transcriptional Mechanisms-Regulation of CXCL10 has been reported previously to be mediated via both transcriptional and posttranscriptional mechanisms (38); therefore, we investigated whether costimulation with TNF␣ and IFN␥ affect CXCL10 mRNA stability. As can be seen in Fig.…”

Section: Tnf␣ and Ifn␥ Synergistically And Transcriptionallymentioning

confidence: 99%

TNF and IFN Synergistically Enhance Transcriptional Activation of CXCL10 in Human Airway Smooth Muscle Cells via STAT-1, NF- B, and the Transcriptional Coactivator CREB-binding Protein

Clarke

Clifford

Jindarat

et al. 2010

Journal of Biological Chemistry

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Asthmatic airway smooth muscle (ASM) expresses interferon-␥-inducible protein-10 (CXCL10), a chemokine known to mediate mast cell migration into ASM bundles that has been reported in the airways of asthmatic patients. CXCL10 is elevated in patients suffering from viral exacerbations of asthma and in patients with chronic obstructive pulmonary disease (COPD), diseases in which corticosteroids are largely ineffective. IFN␥ and TNF␣ synergistically induce CXCL10 release from human ASM cells in a steroid-insensitive manner, via an as yet undefined mechanism. We report that TNF␣ activates the classical NF-B (nuclear factor B) pathway, whereas IFN␥ activates JAK2/STAT-1␣ and that inhibition of the JAK/STAT pathway is more effective in abrogating CXCL10 release than the steroid fluticasone. The synergy observed with TNF␣ and IFN␥ together, however, did not lie at the level of NF-B activation, STAT-1␣ phosphorylation, or in vivo binding of these transcription factors to the CXCL10 promoter. Stimulation of human ASM cells with TNF␣ and IFN␥ induced histone H4 but not histone H3 acetylation at the CXCL10 promoter, although no synergism was observed when both cytokines were combined. We show, however, that TNF␣ and IFN␥ exert a synergistic effect on the recruitment of CREB-binding protein (CBP) to the CXCL10, which is accompanied by increased RNA polymerase II. Our results provide evidence that synergism between TNF␣ and IFN␥ lies at the level of coactivator recruitment in human ASM and suggest that inhibition of JAK/STAT signaling may be of therapeutic benefit in steroid-resistant airway disease.Lung diseases such as asthma and COPD 2 cause significant morbidity and mortality in Western societies. 5-10% of the asthmatic population are unresponsive to corticosteroids, the mainstay for asthma therapy, and patients with COPD are treated ineffectively with steroids. Additionally, viral exacerbations of asthma are a major cause of morbidity and mortality associated with asthma and are relatively unresponsive to steroids (1, 2).CXCL10, a member of the CXC chemokine subfamily, is a potent chemoattractant for mast cells and T lymphocytes, cells implicated in the pathophysiology of asthma and COPD. CXCL10 is elevated in the airways of asthmatic patients and has been implicated in mast cell migration to the ASM bundles (3). CXCL10 also is elevated in the bronchial mucosa and broncho alveolar lavage (BAL) fluid of subjects with moderate/severe asthma, which is largely steroid-resistant (4). Enhanced CXCL10 secretion also has been demonstrated in COPD (5-7), and more recently, it has been reported that serum CXCL10 levels are increased to a greater extent in asthmatics with acute virus-induced asthma compared with nonvirus-induced acute asthma, and increased levels are predictive of virus-induced asthma exacerbations (8). CXCL10 is released in response to IFN␥ or TNF␣ from a number of inflammatory cell types (6, 9 -12), and several reports also have shown that TNF␣ and IFN␥ synergistically enhance CXCL10 release (13-16). Given the he...

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PDGF Synergistically Enhances IFN-γ-Induced Expression of CXCL10 in Blood-Derived Macrophages: Implications for HIV Dementia

Cited by 44 publications

References 70 publications

Trophoblast-Induced Changes in C-X-C Motif Chemokine 10 Expression Contribute to Vascular Smooth Muscle Cell Dedifferentiation During Spiral Artery Remodeling

Trophoblast-Induced Changes in C-X-C Motif Chemokine 10 Expression Contribute to Vascular Smooth Muscle Cell Dedifferentiation During Spiral Artery Remodeling

Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production

TNF and IFN Synergistically Enhance Transcriptional Activation of CXCL10 in Human Airway Smooth Muscle Cells via STAT-1, NF- B, and the Transcriptional Coactivator CREB-binding Protein

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